Tyrosine kinase inhibitor pharmacokinetics

Discrepancies between plasma, serum, whole blood and cellular concentrations of various tyrosine kinase inhibitors

R. Honeywell (1), E. Giovannetti (1), I. Kathman (1), C. Tibaldi (2), F. Cappuzzo (2), J.S. Lind (4), E.F. Smit (4), H.M. Verheul (1), G.J. Peters (1). 
1Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands; 2Division of Oncology, Department of Oncology, Azienda USL-6 of Livorno, Italy; 3Division of Oncology, Department of Oncology, Azienda Ospedaliero-Universitaria of Parma, Italy, 4
Department of Pulmonology, VU University Medical Center, Amsterdam the Netherlands


A relatively new targeted chemotherapeutic treatment consists of a series of small molecules collectively known as tyrosine kinase inhibitors (TKIs). These compounds maintain a similar basic pyrimidine structure, but differ with open or closed rings, fluorinated and/or alkylated side chains. Orally taken daily TKIs develop steady state plasma concentration (SSc) within 2-3 weeks.

These compounds are all hydrophobic and traditional HPLC-UV lacks sensitivity. Using a more sensitive HPLC-MS/MS technique different matrixes (whole blood, serum, plasma and white bloods cells) were tested for analytical interference; the developed assay was utilized for two phase I-II investigations involving gefitinib, erlotinib sunitinib and sorafenib.  Additionly the technique will also measure sunitinib, axitinib, dasatinib, imatinib, lapatinib, nilotinib, vatalanib, vandetanib and tandutinib.

Comparison of the plasma : serum : whole blood SSc revealed a significant difference in the total concentration. Average plasma concentration was as previously reported in literature (Gefitinib - 0.2 ± 0.2 µM; Erlotinib - 2.3 ± 1.6 µM; Sunitinib - 0.13 ± 0.11 µM ; Sorafenib - 1.9 ± 1.1 µM), however serum concentration was 10 fold higher for sorafenib (11.1 ± 7.8 µM) but not for Erlotinib (1.9 ± 1.3 µM) or sunitinib (0.11 ± 0.10 µM ) and whole blood concentration were 100 fold higher for Gefitinib (50.5 ± 62.9 µM) and 200 fold higher for Erlotinib (539.8 ± 182.5 µM). In various tumor cell lines concentrations ranged between 42 - 1266 , 0.0 - 0.001, 25 - 4663.8  and 121.5 - 1412.0 pmol / µg protein for gefitinib, erlotinib, sunitinib and sorafenib, respectively after 6 hours of IC50 concentrations.

These results indicate that the measured plasma concentration is not an accurate reflection of the total systemic exposure and could have significant clinical implications.